One of our major projects is a laboratory-session-based interventional study of heavy social drinkers, with real-world outcome measures. We are harnessing a property of memory called reconsolidation, whereby recently activated memories become briefly vulnerable to disruption. The memories in this instance are the Pavlovian associations that link alcohol-related cues to the responses of craving and drinking. In a procedure called retrieval-extinction, we reactivate those associations through actual intoxication (using each participants favorite drink); then we disrupt them with repeated exposure to personalized drinking-related stimuli. Data from other investigators, in smokers and heroin users, have shown that this procedure can lead to a remarkably generalizable unlinking of cues from craving even after people leave the laboratory setting and return to their usual environments. We are testing that with the smartphone-based daily assessments that have become our units specialty. The protocol is ongoing. Another major project is to develop Just-in-Time Adaptive Interventions (JITAIs) for treatment of substance-use disorders. This is the next major outgrowth of our work with ambulatory assessment of heroin and cocaine users - an ambulatory treatment via smartphone app. For JITAIs, the first goal is to hone content of the intervention. We are preparing to do that with perhaps the most purely psychotherapeutic protocol ever conducted at the NIDA IRP, using both cognitive-behavioral therapy and a mindfulness-based approach called ACT (Acceptance and Commitment Therapy). Our use of these psychotherapies comes with two innovations, one technological (delivery mostly via text on smartphones) and the other methodological (delivery is microrandomized, such that we can test which approach is most immediately helpful under which circumstances in daily life). The protocol is SRC-approved and IRB-approved, and our IT department is programming the app. We will start with a formative-research phase in which we interview opioid and cocaine users about their preferences for a mobile-treatment app. This will lead to a clinical trial. A postdoc with a Ph.D. in social work is joining our group this summer; she will lead the formative interviews and the ongoing content development. The other major component of a JITAI is predictive analytics, so that momentary interventions can be pushed when and where the patient needs them. We are finishing a manuscript that reports on our progress in that realm. The next step is to collect denser momentary data that we can feed into our machine-learning models to generate more accurate predictions. We will soon be amending one of our ongoing EMA protocols to enroll participants for that. A third project is a translational human study that we developed in collaboration with preclinical investigators at the NIDA IRP and extramural addiction researchers. It derives from NIDA IRP work with orbitofrontal mechanisms of decision-making in rats, and from adaptation of that work for healthy human volunteers in neuroimaging studies by extramural scientists. Here, the methods and outcome measures are entirely behavioral. We are assessing whether people with opioid-use disorder are detectably impaired in a type of low-level associative learning called outcome inferencing, and whether that impairment is associated with their patterns of opioid use. There is no treatment component in the protocol itself, but the knowledge gained will inform our future treatment studies. This protocol is under way. A fourth project, in collaboration with Dr. Vera Spagnolo of NIAAA, is to test rTMS as an adjunct to agonist maintenance in OUD. This protocol is in development. A fifth project, in collaboration with Dr. Patrick Finan at the Hopkins Psychiatry Department is a human laboratory study to assess the effects of sleep disruption on opioid abuse liability in people with chronic pain. This is a step toward a new approach toward prevention of iatrogenic OUD, using sleep disruption as a modifiable ongoing risk factor. A sixth project, in collaboration with a small pharmaceutical company. is a human laboratory study to test the safety and efficacy of a biased mu agonist for prevention and relief of opioid withdrawal in people with OUD. This is initial proof of concept for what we hope will be an addition to the choices now available for opioid maintenance treatment of OUD. The niche for a biased agonist is that it could have the easy induction and no-ceiling effectiveness of methadone while also being comparatively free of side effects such as constipation, sedation, and respiratory suppression. The protocol has passed NIH scientific review and is now being reviewed by the FDA. A seventh project, in collaboration with a small technology company., is a combined human laboratory study and field trail for a wearable respiration monitor that may be able to detect psychological stress. This would be integrated with our predictive-analytic work to help push JITAI content at appropriate moments. The protocol amendment incorporating this study has been approved by the IRB, and we are preparing the necessary software.